Interaction of 3-Chloro-2-halopropenyl Ketones with β-Aminocrotonic Acid Ethyl Ester

Abstract

The reaction of 3-chloro-2-halo-1-propenyl ketones with β-aminocrotonic acid ethyl ester leads to the formation of ethyl esters of benzyl, was established that at increased temperatures the compounds obtained are partially converted into the corresponding dihydrofuro [3,4-c]pyridines.The interaction of 2,3-dichloropropyl alkyl ketones with alkyl esters of aminoacetic acid leads to the preparation of 1-alkoxycarbonylmethyl-2-alkylpyrroles [1], but in the case of the interaction of β-chlorovinyl ketones with β-aminocrotonic acid ethyl ester it leads to nicotinic acid ethyl esters [2]. We have also established that the interaction of 2,3-dichloropropenyl alkyl ketones with β-aminocrotonic acid ethyl ester leads to the preparation of ethyl esters of 6-alkyl-4-chloromethyl-2-methylnicotinic acids [3].However further investigations showed that during the vacuum distillation of the products of this reaction, together with the ethyl esters of 6-alkyl-4-chloromethyl-2-methylnicotinic acids 2a-e, starting with R ≥ C 2 H 5 , partial conversion of the latter into 6-alkyl-4-methyl-2-oxo-1,2-dihydrofuro[3,4-c]pyridines 3b-d occurs. It was established that in a series of ethyl esters of 6-alkyl-4-chloromethyl-2-methylnicotinic acids the yield of lactones 3 increases sharply with an increase in radical R. For example, on distilling nicotinic acid derivatives 2a-e lactones 3b 8, 3c 15, 3d 24, and 3e 36% were formed as by-products. An explanation of this might be the fact that depending on the increase in alkyl radical the boiling point of the compound being distilled increases and with it the probability of thermal intramolecular cyclization of compounds 2a-e is increased. When distilling the ethyl esters of 6-benzyl(phenyl, p-tolyl, p-chlorophenyl, cyclohexyl)-4-chloromethyl-2-methylnicotinic acids 2f-j complete lactonization was observed (Scheme 1).With the aim of preventing intramolecular cyclization of compounds 2f-j into lactones the appropriate 6-benzyl (phenyl, p-tolyl, p-chlorophenyl, cyclohexyl)-derivatives of nicotinic acid were isolated and identified as the hydrochlorides.The reaction was carried out in ether or methanol in the presence of an equimolar quantity of triethylamine at 35-40°C for 5 h and the ethyl esters of 6-alkyl(aryl, benzyl, cyclohexyl)-4-chloromethyl-2-methylnicotinic acids 2a-j or their hydrochlorides were obtained in 57-84% yield.On distilling the nicotinic acid derivatives 2a-e at a residual pressure of 20-30 mm Hg they were completely converted into the corresponding lactones 3a-e.